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PLoS One. 2014 Jan 9;9(1):e83987. doi: 10.1371/journal.pone.0083987. eCollection 2014.

TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.

Author information

1
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
2
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, United Kingdom ; Department of Hepatology, Barts Health NHS Trust, London, United Kingdom.
3
Departments of Exploratory Science, Discovery Biology, and Validation Biology, Biogen Idec Inc., Cambridge, Massachusetts, United States of America.
4
Department of Physiology, Faculty of Medicine, University of the Basque Country, Bilbao, Spain.

Abstract

BACKGROUND & AIMS:

Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH.

METHODS:

To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies.

RESULTS:

In WT mice, rare Fn14(+) cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12-8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes.

CONCLUSIONS:

TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy.

PMID:
24416188
PMCID:
PMC3886973
DOI:
10.1371/journal.pone.0083987
[Indexed for MEDLINE]
Free PMC Article

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